The overall goal of this proposal is to define mechanisms of neuronal injury following focal and global cerebral ischemia in adult and pediatric animals, and to define developmental cerebrovascular regulation in fetal and newborn animals. The Program represents a multidisciplinary, mechanistic approach involving interactive, productive investigators with complimentary areas of expertise who have long been committed to studies of the cerebral circulation and ischemia. One major aim will be to integrate the activities of various disciplines such that the interrelationships will result in a greater scientific contribution than could be achieved if each project were pursued individually. The Program has two themes: first, molecular, neuropathologic, physiologic and neurobehavioral approaches are proposed to examine the mechanisms of neuronal injury and neuroprotection from stroke and cardiac arrest/CPR (focal and global cerebral ischemia). We will determine the neuroprotective mechanisms associated with sigma receptor signaling, estrogen, and superoxide dismutase/nitric oxide. Also, developmental cerebrovascular regulation focusing on mechanisms of vasodilation will be characterized in the fetus and newborn. Second, state-of-the-art molecular, neuropathology, physiology and neurobehavioral approaches are used throughout the Program. The Program has several important strengths: first, the investigators have a long history of interactive studies of the brain and its vasculature under normal and pathophysiological conditions. Our preliminary data indicate feasibility of our new approaches and demonstrate evidence of integration of the new additions to the Program. Third, the investigators are leaders in the field concerning mechanisms of neuronal injury, cerebrovascular regulation, and ischemia. Fourth, the investigators use sophisticated physiological approaches and molecular, neuropathological and neurobehavioral approaches have been incorporated to facilitate novel insight into neuronal injury and cerebrovascular regulatory mechanisms. The Program consists of four projects: 1) Sigma Receptor Signaling in Focal Cerebral Ischemia; 2) Gender Differences in Stroke; 3) Cardiac Arrest and Resuscitation: Mechanisms of Brain Injury; and 4) Developmental Cerebrovascular Regulation in the Fetus and Newborn, and is supported by four Core facilities: 1) Administration; 2) Neuropathology; 3) Neurochemistry; and 4) Neurobehavior.